Topoisomerase I is an enzyme that plays important and critical role in cellular proliferation. In particular, topoisomerase I catalyzes the uncoiling of DNA during replication and transcription. See Pommier et al. (1998) Biochim. Biophys. Acta. 1400(1-3):83-105 and Wang (1996) Annu. Rev. Biochem. 65:635-92). Thus, by inhibiting this enzyme, highly proliferative cells are preferentially targeted and unable to propagate. As a consequence, this enzyme is a highly attractive target for chemotherapeutic agents, especially in human cancers.
The activity of topoisomerase I is regulated by phosphorylation, primarily on serine residues [Turman et al. (1993) Biochem. Med. Metab. Biol. 50(2):210-25; Coderoni et al. (1990) Int. J. Biochem. 22(7):737-46; Kaiserman et al. (1988) Biochemistry 27(9):3216-22; Samuels et al. (1992) J. Biol. Chem. 267(16): 1156-62)], and appears to be necessary for the initial complex formation between the enzyme and DNA (Coderoni et al. (1990) Int. J. Biochem. 22(7):737-46).
The poly (ADP-ribose) polymerase (“PARP”) family of enzymes plays a critical role in the maintenance of DNA integrity by binding to DNA and repairing single strand breaks (known as “nicks”). PARP1 is overexpressed in a variety of cancers, and its expression has been associated with overall prognosis in cancer, especially breast cancer. PARP inhibitors are believed to bind to PARP, thereby inhibiting its DNA-repair activity as well as preventing the release of PARP from DNA. Inhibition of the activity of PARP1, and a related isoform, PARP2 has shown clinical activity in a several cancers. Kunmar et al. (2012) BMC Medicine 10(25):1-5.
Although both topoisomerase I inhibitors, PARP inhibitors and other antineoplastic agents have been proposed to treat patients suffering from cancer with varying degrees of success, one in four deaths in the United States is due to cancer. Siegel et al. (2013) CA Cancer J. Clin. 63:11-30. Although treatment regimens involving a single antineoplastic agent are often sought, combinations of known antineoplastic agents can be highly effective as well. Thus, there remains a need to provide (among other things) treatment regimens where combination strategies show enhanced efficacy.
The present invention seeks to address these and other needs in the art.